Muscle lipid accumulation and protein kinase C activation in the insulin-resistant chronically glucose-infused rat

Chronic glucose infusion results in hyperinsulinemia and causes lipid accum ulation and insulin resistance in rat muscle. To examine possible mechanism s for the insulin resistance, alterations in malonyl-CoA and long-chain acy l-CoA (LCA-CoA) concentration and the distribution of protein kinase C (PKC ) isozymes, putative links between muscle lipids and insulin resistance, we re determined. Cannulated rats were infused with glucose (40 mg.kg(-1).min( -1)) for 1 or 4 days. This increased red quadriceps muscle LCA-CoA content (sum of 6 species) by 1.3-fold at 1 day and 1.4-fold at 4 days vs. saline-i nfused controls (both P < 0.001 vs. control). The concentration of malonyl- CoA was also increased (1.7-fold at 1 day, P < 0.01, and 2.2-fold at 4 days , P < 0.001 vs. control), suggesting an even greater increase in cytosolic LCA-CoA. The ratio of membrane to cytosolic PKC-epsilon was increased twofo ld in the red gastrocnemius after both 1 and 4 days, suggesting chronic act ivation. No changes were observed for PKC-alpha, -delta, and -theta. We con clude that LCA-CoAs accumulate in muscle during chronic glucose infusion, c onsistent with a malonyl-CoA-induced inhibition of fatty acid oxidation (re verse glucose-fatty acid cycle). Accumulation of LCA-CoAs could play a role in the generation of muscle insulin resistance by glucose oversupply, eith er directly or via chronic activation of PKC-epsilon.